Study of Everolimus (RAD001) in Patients With Recurrent Glioblastoma Multiforme (GBM)
- Registration Number
- NCT00515086
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
This study will define the safety and efficacy of Everolimus (RAD001) administered daily in patients with glioblastoma multiforme (GBM)
- Detailed Description
This was a multicenter, open label, randomized study of RAD001 dosed daily in patients with recurrent GBM. The study was conducted with 2 parallel groups of patients. Group 1 was designed to study the biological effects of RAD001 in patients scheduled to undergo salvage surgical resection, and Group 2 was to enroll patients who were not scheduled for surgery. Patients in Group 1 were randomly assigned to one of three pre-surgery treatment groups (0, 5 or 10 mg/day RAD001 for 7 days). All patients in Group 2 were to receive a fixed daily dose of 10 mg/day oral RAD001.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 41
- Age 18 years of age or older
- Histologically confirmed Glioblastoma Multiforme (GBM)
- Radiographic evidence of disease progression
- Patients must have evaluable contrast enhancing tumor
- Availability of paraffin blocks or unstained pathology slides for biomarker studies
- Karnofsky Performance Status of greater than or equal to 60%
- Prior treatment with Mammalian target of rapamycin (mTOR) inhibitor
- History of another malignancy within 3 years
- Cardiac pacemaker
- Ferromagnetic metal implants other than those approves as safe for use in Magnetic resonance imaging (MRI) scanners
- Claustrophobia
- Obesity
- Unstable systemic diseases
- Elevated cholesterol or triglycerides
- Radiation therapy or cytotoxic chemotherapy <=4 weeks prior to study enrollment. Patient must have recovered from the toxic effects of a prior chemotherapy.
- Patients must be off all enzyme inducing anticonvulsants for at least 2 week before study enrollment can occur
- Need for increasing dose of steroids. Patients on a stable or tapering dose of steroids >=7 days were permitted.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Everolimus 10 mg + Surgery Surgery Participants scheduled to undergo salvage surgical resection received a daily oral dose of 10 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity. Everolimus 5 mg + Surgery Surgery Participants scheduled to undergo salvage surgical resection received a daily oral dose of 5 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity. Everolimus 0 mg + Surgery Everolimus Participants scheduled to undergo salvage surgical resection received no treatment with Everolimus prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity. Everolimus 0 mg + Surgery Surgery Participants scheduled to undergo salvage surgical resection received no treatment with Everolimus prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity. No Surgery (Everolimus 10 mg) Everolimus Participants with recurrent Glioblastoma Multiforme (GBM) not scheduled to undergo salvage surgical resection, received a daily oral dose of 10 mg Everolimus (RAD001) until evidence of disease progression or toxicity. Everolimus 10 mg + Surgery Everolimus Participants scheduled to undergo salvage surgical resection received a daily oral dose of 10 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity. Everolimus 5 mg + Surgery Everolimus Participants scheduled to undergo salvage surgical resection received a daily oral dose of 5 mg Everolimus for 7 days prior to surgery, then after recovery from surgery received a 10 mg daily oral dose of Everolimus until evidence of disease progression or toxicity.
- Primary Outcome Measures
Name Time Method Surgery Group: Percentage Change From the Baseline in S6 Kinase Levels Baseline and Day 7-9 (during salvage surgery) In the Surgery Group, the primary efficacy assessment was inhibition of Mammalian target of rapamycin (mTOR) as defined as ≥75% S6 phosphorylation. The occurrence of S6 phosphorylation was determined by phosphor-S6 immunohistochemical staining. Tumor cells from the initial surgical resection and from the salvage resection were used for assessments.
No Surgery Group: Best Overall Tumor Response First day of treatment to study discontinuation (up to 60 weeks) The best overall tumor response is reported for participants with 1 previous relapse and participants with ≥2 previous relapses according to the following categories: Complete Response, Partial Response, Stable Disease and Progressive Disease. Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) was used for tumor analysis. The objective assessment of tumor response was evaluated at each site by the designated pathologist based on the Neuro-Oncology criteria for Tumor Response for Central Nervous System (CNS) tumors.
- Secondary Outcome Measures
Name Time Method Surgery Group: Blood and Brain Tissue Levels of Everolimus (RAD001) Baseline and Day 7-9 (Blood samples were collected one day prior to surgery and tissue samples were collected during surgery.) Surgery Group: Progression-free Survival After surgery (within 96 hours), Weeks 4 and 8 and then every 8 weeks after restarting treatment until study discontinuation (Up to 28 weeks) Progression-free survival (PFS) was assessed using Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) and based on the Neuro-Oncology Criteria for Tumor Response for CNS tumors. PFS was measured from the first day of treatment after surgery to disease progression or death and is derived using the Kaplan-Meier method.
Surgery Group: Biomarkers Phosphatase and Tensin Homolog (PTEN) and Epidermal Growth Factor Receptor (EGFR) After surgery, week 4, week 8 and every 8 weeks thereafter The secondary efficacy assessment was to evaluate the role of PTEN and EGFR pathway status on phosphor-S6. Tumor cells from the initial surgical resection and from the salvage resection were used for assessments. Immunohistochemistry and Fluorescence in-situ hybridization (FISH) were used to assess PTEN and EGFR pathway status.
Study was terminated due to slow enrollment. Analysis was not possible due to insufficient sample size.No Surgery Group: Progression Free Survival First day of treatment to study discontinuation (up to 60 weeks) Progression-free survival (PFS) was assessed using Gadolinium chelate-enhanced Magnetic Resonance Imaging (MRI) and based on the Neuro-Oncology Criteria for Tumor Response for CNS tumors. PFS is reported for participants with 1 previous relapse and participants with ≥2 previous relapses. PFS was measured from the first day of treatment to disease progression or death and is derived using the Kaplan-Meier method.
Surgery Group: Number of Participants With Adverse Events First day of treatment to study discontinuation (Up to 28 weeks) The number of participants with any adverse event by System Organ Class. Additional information about Adverse Events can be found in the Adverse Event Section.
Trial Locations
- Locations (8)
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Duke University - Preston Robert Tisch Brain Tumor Center
🇺🇸Durham, North Carolina, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
UCLA
🇺🇸Los Angeles, California, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States